Expansion of Tumor-Infiltrating CD8+ T cells Expressing PD-1 Improves the Efficacy of Adoptive T-cell Therapy

Fernandez-Poma, Sarita M.; Salas‐Benito, Diego; Lozano, Teresa; Casares, Noëlia; Riezu-Boj, José Ignacio; Mancheño, Uxua; Elizalde, Edurne; Alignani, Diego; Zubeldia, Natalia; Otano, Itziar; Conde, Enrique; Sarobe, Pablo; Lasarte, Juan José; Hervás-Stubbs, Sandra

doi:10.1158/0008-5472.can-17-0236

Cited by 108 publications

(81 citation statements)

References 40 publications

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“…[4] Tumor-infiltrating lymphocytes are a key for good clinical outcomes and prediction of the response to existing checkpoint inhibitors. [5, 6] However, in vivo studies suggest the axis plays a tumorigenic role as well by increasing tumor proliferation and metastasis. [7, 8] Thus, a better understanding of this axis in the tumor environment is necessary to discover its role as a potential target for immunotherapy or as a predictive indicator for existing cancer treatments.…”

Section: Introductionmentioning

confidence: 99%

CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation – A target for novel cancer therapy

Tokunaga

Zhang

Naseem

et al. 2018

Cancer Treatment Reviews

1,012

779

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Chemokines are proteins which induce chemotaxis, promote differentiation of immune cells, and cause tissue extravasation. Given these properties, their role in anti-tumor immune response in the cancer environment is of great interest. Although immunotherapy has shown clinical benefit for some cancer patients, other patients do not respond. One of the mechanisms of resistance to checkpoint inhibitors may be chemokine signaling. The CXCL9, -10, -11/CXCR3 axis regulates immune cell migration, differentiation, and activation, leading to tumor suppression (paracrine axis). However, there are some reports that show involvements of this axis in tumor growth and metastasis (autocrine axis). Thus, a better understanding of CXCL9, -10, -11/CXCR3 axis is necessary to develop effective cancer control. In this article, we summarize recent evidence regarding CXCL9, CXCL10, CXCL11/CXCR3 axis in the immune system and discuss their potential role in cancer treatment.

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Section: Introductionmentioning

confidence: 99%

CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation – A target for novel cancer therapy

Tokunaga

Zhang

Naseem

et al. 2018

Cancer Treatment Reviews

1,012

779

View full text Add to dashboard Cite

show abstract

“…Together, these results suggest that PD-1 might be a useful biomarker for tumour-reactive TILs enrichment. This concept was supported by the studies on murine model of melanoma, indicating that treatment with sorted and expanded PD-1+ TILs improved ACT efficacy compared to unsorted TILs [103].…”

Section: Enrichment Of T Cells Expressing Markers Of Activationmentioning

confidence: 85%

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

Chruściel

Urban-Wójciuk

Arcimowicz

et al. 2020

Cancers

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In recent years, much research has been focused on the field of adoptive cell therapies (ACT) that use native or genetically modified T cells as therapeutic tools. Immunotherapy with T cells expressing chimeric antigen receptors (CARs) demonstrated great success in the treatment of haematologic malignancies, whereas adoptive transfer of autologous tumour infiltrating lymphocytes (TILs) proved to be highly effective in metastatic melanoma. These encouraging results initiated many studies where ACT was tested as a treatment for various solid tumours. In this review, we provide an overview of the challenges of T cell-based immunotherapies of solid tumours. We describe alternative approaches for choosing the most efficient T cells for cancer treatment in terms of their tumour-specificity and phenotype. Finally, we present strategies for improvement of anti-tumour potential of T cells, including combination therapies.

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“…Recognition of neoantigens by TILs is supported by clinical findings demonstrating that successful immune checkpoint blockade therapy is correlated with high mutation loads in tumor cells [7][8][9][10]. That CD8 + PD1 + T cells are enriched in the tumor microenvironment also supports a role for neoantigen-specific TILs as mediators of immune checkpoint blockade [11,12].…”

Section: Introductionmentioning

confidence: 91%

Very rapid cloning, expression and identifying specificity of T-cell receptors for T-cell engineering

Zong

Flores

et al. 2020

PLoS ONE

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Neoantigens can be predicted and in some cases identified using the data obtained from the whole exome sequencing and transcriptome sequencing of tumor cells. These sequencing data can be coupled with single-cell RNA sequencing for the direct interrogation of the transcriptome, surfaceome, and pairing of αβ T-cell receptors (TCRαβ) from hundreds of single T cells. Using these 2 large datasets, we established a platform for identifying antigens recognized by TCRαβs obtained from single T cells. Our approach is based on the rapid expression of cloned TCRαβ genes as Sleeping Beauty transposons and the determination of the introduced TCRαβs' antigen specificity and avidity using a reporter cell line. The platform enables the very rapid identification of tumor-reactive TCRs for the bioengineering of T cells with redirected specificity.immunotherapy is that ex vivo culture and numeric expansion typically leads to the clonal and/ or oligoclonal expansion of terminally differentiated T cells. Together, these clinical data suggest that the administration of "young" T cells that are sourced from peripheral blood and genetically modified to be neoantigen-specific offers an advantage over TIL-based immunotherapy.The bioengineering of neoantigen-specific T cells requires identifying individual TCRαβs and determining their antigen specificity. Next-generation sequencing (NGS) was used to identify non-synonymous tumor-specific mutations and single-cell RNA sequencing (scRNAseq) to identify paired full-length TCRαβ sequences [18]. This enabled us to reconstruct tumor-specific TCRs and evaluate their antigen specificity to engineer clinical-grade T cells. This was undertaken by very rapidly constructing a library of TCRαβ genes expressed in DNA plasmids from the Sleeping Beauty (SB) transposon/transposase system and then inducing the expression of cloned TCRαβs in a reporter cell line to determine their antigen specificity and avidity. These reporter cells were co-cultured with genetically edited HLA null HEK293 cells and genetically modified with monoallelic HLA and the putative neoantigen as a minigene construct to serve as artificial antigen-presenting cells. This suite of technologies could be used to determine the antigen specificity of TCRs retrieved from primary tumors. In summary, this platform serves as a resource for the very rapid, robust, and high-throughput identification of immunogenic neoantigens and their cognate antigen-specific TCRs. Materials and methods Ethical statementPeripheral blood mononuclear cells (PBMCs) were obtained from patients who had provided written informed consent in accordance with a protocol established and approved by MD Anderson's Institutional Review Board (#LAB07-0296, Acquisition of Peripheral Blood from Healthy Donors). The identities of all patients were kept private. Animals were handled in accordance with strict guidelines established by MD Anderson's Institutional Animal Care and Use Committee (IACUC), which specifically approved this study (#00001131-RN02, Adoptive Immunotherapy w...

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Expansion of Tumor-Infiltrating CD8+ T cells Expressing PD-1 Improves the Efficacy of Adoptive T-cell Therapy

Cited by 108 publications

References 40 publications

CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation – A target for novel cancer therapy

CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation – A target for novel cancer therapy

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

Very rapid cloning, expression and identifying specificity of T-cell receptors for T-cell engineering

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